Segregating neuronal and glial membrane injury in an anti-GM1 antibody-mediated neuropathy

Campbell, Clare Ile (2022) Segregating neuronal and glial membrane injury in an anti-GM1 antibody-mediated neuropathy. PhD thesis, University of Glasgow.

Abstract

Guillain-Barré syndrome is a post-infectious autoimmune disorder affecting the peripheral nervous system. Broadly, it presents as acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP). Although segmental demyelination is the predominant characteristic of AIDP, secondary bystander axonal injury can occur and is associated with poor prognosis. The pathogenesis of AIDP and secondary bystander axonal injury are poorly understood in comparison to the established mechanisms involved in primary axonal degeneration in AMAN. The most common preceding infection is with Campylobacter jejuni which is associated with anti-GM1 ganglioside autoantibodies. GM1 antibodies primarily bind to the motor axolemma but have also been demonstrated to bind to the paranodal Schwann cell loops. It is currently unknown whether the pathological phenotype mediated by anti-GM1 antibodies arises from injury to one or other, or both membranes in AMAN and AIDP. Current animal models are unable to segregate primary injury from the consequences of cell-specific membrane injury because GM1 is expressed on both neural membranes. To address this, we used GalNAc-T-/--Tg(neuronal) and GalNAc-T-/--Tg(glial) mice to selectively target the axonal and glial membrane, respectively, with a single anti-GM1 antibody. We investigated the effects of complement-mediated injury at the distal motor neuromuscular junction (NMJ) and distal node of Ranvier (NoR). Results demonstrated that injury to the axonal membrane in GalNAc-T-/--Tg(neuronal) mice resulted in a significant reduction of axonal integrity at the NMJ and disruption to voltage gated sodium channels at the NoR. In contrast, it was established that targeted injury to the glial membrane caused significant impairment to the axo-glial junction at the paranode, resulting in disruption to the paranodal loops. Complement inhibition attenuated injury to the paranodal loops, suggesting that targeting the complement pathway therapeutically would be effective in treating demyelinating neuropathies. Furthermore, targeted injury to the glial membrane subsequently led to secondary injury to the axon at the distal NoR. Overall, these transgenic mice offer many potential roles in the investigation of anti-ganglioside antibody mediated binding and injury at specific membrane sites; particularly to study the downstream mechanism(s) of primary and secondary axonal degeneration to help inform the development of targeted treatments.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from Argenx.
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Willison, Professor Hugh and McGonigal, Dr. Rhona
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-82735
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 04 Mar 2022 12:38
• Last Modified: 11 Apr 2022 09:30
• Thesis DOI: 10.5525/gla.thesis.82735
• URI: https://theses.gla.ac.uk/id/eprint/82735